Lowering of Central Aortic Blood Pressure—Not All Antihypertensive Agents Are Created Equal
Authors: Williams B., Lacy P.S., Thom S.M., Cruickshank K., Stanton A., Collier D., Hughes A.D., Thurston H., O’Rourke M
Journal: Journal of the American Society of Nephrology (2006)

It had been known for considerable time that because of the propagation of the pressure wave in the elastic central conduit arteries, the instantaneous pressure is not uniform throughout the central conduit arteries (1). It has only been relatively recently, however, that the potential clinical relevance of this phenomenon has been recognized and that adequate methodology has been developed to further look into this problem (2,3). One spin-off of this debate has been the recognition that blood pressure (BP) measured in the brachial artery may differ to a variable degree from the pressure existing in the aorta, that this pressure difference is affected by age and disease states and that antihypertensive agents differ with respect to their impact on the BP difference between brachial and central aortic pressures. Despite the remarkable findings in some smaller studies (4–6), what had been lacking so far was well-documented evidence of this phenomenon in a sufficiently large cohort and proof that the results impact on clinical outcomes. The ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study was designed to compare “conventional” antihypertensive agents, i.e., β blockers and diuretics (Atenolol±thiazide-based diuretics) with more “modern” antihypertensive drugs, i.e., a calcium channel blocker and ACE inhibitor (Amlodipin±Perindopril). The outcome of the primary study had been published before (7), which documented the superiority of the Amlodipin/Enalapril combination on fatal and nonfatal stroke, total cardiovascular events, and procedures, as well as on all-cause mortality, although the difference was not significant for the primary endpoint of nonfatal myocardial infarction and fatal chronic heart disease. In an effort to further elucidate potential mechanisms accounting for any differences between the two antihypertensive strategies despite no differences in BP as measured conventionally at the level of the brachial artery (“beyond BP”), Bryan Williams and colleagues examined in a preplanned substudy (Conduit Artery Function Evaluation [CAFE] study) whether the two antihypertensive strategies differed with respect to their effect on central pressure relative to peripheral arterial BP (8). To this end, out of the total of 19,257 patients in the ASCOT study in 5 study centers, 2199 patients with systolic BP >160 mmHg, diastolic BP >100 mmHg, or treated BP >140 mmHg systolic or >90 mmHg diastolic, and with additional cardiovascular risk factors were entered into the CAFE substudy and followed for 3 years. The study had a PROBE design (prospective, randomized, open, blinded end point evaluation). The brachial BP was measured with the semiautomated oscillometric Omron 705CP device. The calculation of the derived central pressure was based on measurements using radial artery applanation tonometry (SphygmoCor) and calculation with a dedicated software applying a validated transfer function. In addition, pulse wave analysis was performed in a subset of patients. A comment concerning the rationale behind the study may be appropriate. The central aortic pressure (and by implication the pressure determining coronary and renal perfusion) is not simply given as the ratio between cardiac output and peripheral vascular resistance according to the law of Ohm. Rather, the time-dependent pressure wave is modified by the elastic properties of the central arteries and, in addition, by the backreflection of the outgoing wave in the periphery, which is then superimposed on the outgoing central pulse wave in late systole and can be quantitated by calculating the augmentation index (5). In young individuals with no structural or functional changes of the central arteries, the difference between peripheral and central BP is negligible, whereas in elderly subjects or individuals with changes in the structure and function of central vessel walls, the deviation may be substantial and clinically relevant (6,9). Specifically in renal patients, Gerard London showed marked deviations of the pulse profile from normal with exaggerated systolic upstroke secondary to increased stiffness of the vessel wall, and, during late systole, premature return of the pulse wave reflected in the periphery (10). What findings were obtained in the CAFE substudy? At the end of the study the brachial artery pressure values were similar in the two groups on Atenolol±thiazide-based diuretics and on Amlodipin±Perindopril, respectively. The measured radial and the calculated central pulse wave forms were strikingly different, however; in patients treated with Atenolol, the radial pulse wave form was broader with a more prominent late systolic peak. The derived central aortic systolic pressure was substantially lower (by 4.3 mmHg, 3.3 to 5.4, 95% confidence interval) in the group on Amlodipin±Perindopril compared with the group on Atenolol±thiazide-based diuretics. The difference was significant and consistent during repeated measurements with time; there were small differences in central aortic diastolic pressure values as well. As a potential explanation for the higher central aortic pressure in the patients on Atenolol±thiazide-based diuretics compared to the central aortic pressure in patients on Amlodipin±Perindopril, the authors could exclude an increase in the amplitude of the outgoing systolic pressure wave, but a plausible explanation is the increased augmentation of the systolic pressure wave in the aorta; the percent increase in the central systolic pressure wave attributable to wave reflection (augmentation index) was 6.5%. These findings are not an innocent academic exercise, but impact the cardiovascular and renal outcomes in the CAFE study. Using the Cox proportional hazards technique in the different Cox models, each of the following were significantly associated with the composite end point comprising all cardiovascular events and cardiovascular procedures as well as development of renal impairment: calculated central aortic pulse pressure, central aortic pressure wave augmentation, as well as outgoing pressure wave height and brachial pulse pressure (as a crude index of aortic stiffness). Even after adjustment for several baseline confounders, this relation continued to be significant, particularly for central aortic pulse pressure. Why should Atenolol±thiazide-based diuretics cause such impressive changes in wave reflection? The earlier return of the pulse wave is not explained by differences in arterial pulse wave velocity, because the measured pulse wave velocity between the groups on Atenolol±thiazide-based diuretics compared with the group on Amlodipin±Perindopril was not significantly different. Another possibility to consider is that, in the group on Atenolol±thiazide-based diuretics, the outgoing wave is reflected closer to the aorta, thus explaining the earlier return of the wave potentially as a result of arterial vasoconstriction (11) or remodeling (12), or conversely, vasodilatation and remodeling by calcium channel blockers. This interpretation would be in line with the results obtained in the Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind study (REASON) study (13). A final possibility would be that, in patients on β blockers, bradycardia prolonged the ejection time so that the incoming reflected wave was more extensively superimposed upon the outgoing wave (14). The above documented behavior of central pressure and pulse wave contours on β blocker treatment may well explain why in previous studies β blockers—despite similar achieved BP—were inferior to alternative antihypertensive treatments concerning reduction of left ventricular hypertrophy (15), of carotid intima-media thickness (16), as well as modification of resistance artery structure (17–19). Because of the marked abnormalities of the structure and elasticity of central arteries in patients with renal dysfunction (20,21), even at relatively early stages of reduced GFR (22), the above findings are of considerable interest to the nephrologist. Indeed, it has been shown that indices of elasticity of central arteries respond differently to different antihypertensive agents (6,23), and BP-independent effects of ACE inhibitors on aortic elasticity have been shown in renal patients as well (24). Because not only perfusion of the coronary vessels, but also of the vessels of the kidney, is driven by the central—and not by the peripheral—arterial pressure, it is conceivable that some of the superior renoprotection of antihypertensive agents such as ACE inhibitors and angiotensin receptor blockers (25,26) is accounted for, at least in part, by their beneficial effect on central pressure. In the ongoing discussion of whether ACE inhibitors or angiotensin receptor blockers provide renoprotection beyond BP (25,27), it is definitely relevant to consider also the effects of blockade of the renin-angiotensin system on central pressure.